TET2 as a novel epigenetic regulator for uterine function and fertility

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PROJECT SUMMARY Infertility and subfertility are pervasive problems in women, and failure of the endometrial adaptation to an implanting embryo is considered a significant, yet poorly understood, contributing factor. Ten-Eleven Translocation proteins (TETs) are the iron(II)/a-ketoglutarate (Fe(II)/a-KG)-dependent methylcytosine dioxygenases (TET1, TET2 and TET3) that confer active DNA demethylation by the iterative oxidation of 5- methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). TETs can also affect chromatin modifications and gene expression independent of enzymatic activity via interactions with other proteins including transcription factors (e.g., WT1) and epigenetic modifiers (e.g., SIN3A). Emerging evidence suggests that TET proteins may serve as key epigenetic regulators in response to ovarian steroid hormones estrogen (E2) and progesterone (P4) via their cognate nuclear receptors ESR1 and PGR in the regulation of normal uterine function. Our preliminary data in humans and mice has shown that all three TETs are expressed (Tet2>>Tet3>Tet1) in both endometrial epithelial and stromal cells, increased significantly during the window of receptivity but decreased in eutopic endometrium of endometriosis. Given that TET2 ranks among top-mutated genes in female cancers, particularly uterine corpus endometrial carcinoma (UCEC) and uterine carcinosarcoma (UCS), we have generated uterine Tet2-deleted female mice, PgrCre/+Tet2f/f (Tet2d/d). The Tet2d/d mothers were subfertile with normal ovarian and oviductal functions. Therefore, the goal of this proposal is to determine the in vivo role of Tet2 in uterine physiology using conditional Tet2 mutant mouse models. In Aim 1, we will determine the role of Tet2 in regulation of the window of receptivity. In Aim 2, we will determine the role of Tet2 in endometrial stromal cell decidualization in vivo. Completion of these aims will have defined the phenotypic roles of TET2 in the regulation of endometrial physiology, including implantation and decidualization in vivo. In addition, data generated from this mouse work will provide strong support for a future Standard NIH R01/R21 application, addressing the epigenetic mechanisms by which uterine epithelial and/or stromal TET2 regulate uterine function during pregnancy and disease states (e.g., endometriosis and endometrial cancer). Thus, the findings from this research will be important in informing human clinical medicine.